ESRD In Children Research Articles

Non-traditional risk factors of progression of chronic kidney disease in adult population: a scoping review.

Chronic kidney disease (CKD) has become a public health concern over the last several years. Nowadays developed countries spend around 3% of their annual health-care budget on patients with CKD. According to the scientific community the most remarkable risk factors for CKD are diabetes and hypertension. Unknown CKD etiology has been reported as a global phenomenon including uncommon risk factors such as: dehydration, leptospirosis, heat stress, water quality, and others. This study aims to report non-traditional risk factors for ESRD based on a scoping review methodology. The scoping review methodology described by Arksey and O'Malley was used by performing an extensive review of the information. A total of 46 manuscripts were reviewed. The non-traditional ESRD risk factors are depicted based on six categories. Gender and ethnicity have been considered as risk factors for ESRD. Erythematous systemic lupus (ESL) is reported as an important risk factor for ESRD. Pesticide use has been an significant risk factor due to its effects on human and environmental health. Some compounds commonly used in homes against insects and plants are related to ESRD. Congenital and hereditary diseases in the urinary tract have been studied as a cause of ESRD in children and young adults. End-stage renal disease is a major concern for public health on a global level. As it can be seen, non-traditional risk factors are several and have different etiologies. It is necessary to put the issue on the table and add it to the public agenda in order to find multidisciplinary solutions.

Use of continuous ambulatory peritoneal dialysis (CAPD) in the treatment of children with END-stage renal disease

Continuous ambulatory peritoneal dialysis is a form of treatment for end-stage renal disease. This mini-review discusses the use of CAPD as a treatment for ESRD in children. It also discusses the knowledge of the complications of this technique on the effectiveness of the treatment as well as the knowledge of its therapeutic effects. Studies have been collected from electronic rulers (Google scholar /PubMed...) where 30 studies have been studied and analyzed so that these studies included experimenting with CAPD on many children of different age groups. Results of these studies have shown that CAPD is considered an advanced technique for the treatment of ESRD in children, despite many complications such as peritonitis and catheter problems, which are among the most important, but several studies have indicated that the position of the catheter in a surgically controlled manner by specialized physicians mitigates its problems. However, this treatment has many advantages over dialysis. Especially in children, they are freer, more energetic, and more easily able to carry out their activities, especially children who live in remote areas and far from health centers. But we need to think about how to relieve the complications of peritonitis that were common in all the studies that have been done analyzed in this mini-review.

This Month's Highlights.

### Mutated PRDM15 in Galloway-Mowat, Nephrotic Syndromes Proteinuric kidney disease, a leading cause of ESRD in children, is part of Galloway-Mowat syndrome, a rare condition that includes a severe form of progressive nephropathy as well as prominent central nervous system features. The most

Good outcome of the single-center pediatric kidney transplant program in Abu Dhabi.

Renal transplantation is the treatment of choice for ESRD in children. It is associated with better quality of life, growth of children, and improved long-term survival. The aim of the study was to evaluate the outcomes of pediatric renal transplantation at a tertiary care center in UAE. A retrospective chart review was undertaken for all the pediatric renal transplants performed at Sheikh Khalifa Medical City, Abu Dhabi, UAE, over the past 9years. The study evaluated the demographic data, outcomes, and complications of pediatric renal transplantation. The post-transplantation outcomes including surgical complications, documented infections, graft rejection, graft and patient survival, effect on growth, and eGFR were reviewed. Between 2010 and 2018, 30 pediatric patients underwent renal transplantation. The follow-up period ranged from 1 to 9years with a mean of 3.3years. The mean age of the patients at the time of transplant was 9.8years, and 56.7% were males. Prior to the transplantation, the majority of the recipients were on peritoneal dialysis (70.0%). Main source of renal donation at our center was from LRD, chiefly from parents. Patient survival at 1 and 5years was 100% and 96.7%, respectively. Graft survival at 1 and 5years was 96.7% and 83.3%, respectively. During the 9-year follow-up period, 5 (16.7%) recipients experienced rejection episode. This study demonstrates that during 5-year period, pediatric kidney transplantation program has achieved optimal patient (96.7%) and graft (83.3%) survival rates and is comparable to well-established centers.

Non-standard criteria donors in pediatric kidney transplantation.

KT remains the treatment of choice for ESRD in children. However, the demand for kidney transplants continues to outstrip supply, even in the pediatric scenario. We reviewed the applicability of nonSCDs for pediatric KT. There is a lack of studies analyzing this modality among pediatric donors and recipients, where most conclusions are based on predictions from adult data. Nevertheless, marginal donors might be a reasonable option in selected cases. For example, the use of older LDs is an acceptable option, with outcomes comparable to SCDs. Organs donated after cardiac death represent another possibility, albeit with logistic, ethical, and legal limitations in some countries. AKI donors also constitute an option in special situations, although there are no pediatric data on these transplants. Likewise, there are no data on the use of expanded criteria donors in pediatric patients, but this appears not to be a good option, considering the compromised long-term survival.

European Society of Pediatric Nephrology survey on current practice regarding recurrent focal segmental glomerulosclerosis after pediatric kidney transplantation.

Primary FSGS is an important cause of ESRD in children. FSGS recurrence after kidney transplantation is associated with early graft loss. No guidelines for treatment of FSGS recurrence exist. We conducted a survey to gain insight into variation of treatment between centers. A survey was sent to all members of the ESPN on behalf of the "Renal Transplantation" and "Idiopathic Nephrotic Syndrome" working groups. Fifty-nine nephrologists from 31 countries responded, reporting 807 FSGS patients, with 241 (30%) FSGS recurrences after transplantation. Recurrence varied from 0% to 100% between respondents. Native nephrectomy before or during transplantation was performed, respectively, always (37%), never (39%), or on clinical indication (17%). Half of the respondents started preventive treatment before transplantation, using PF (n=10); R (n=4); PF or IA, plus R (n=9); cyclosporine (n=2); or unknown (n=4). Immunosuppressive therapy for patients without known mutations consisted of a combination of steroids, tacrolimus/cyclosporine, and MMF, with or without IL-2R-blockade in, respectively, 61% and 86% of the respondents. Sixty-three percent applied a similar regimen to patients with known mutations. FSGS recurrence was treated with PF or IA, plus R by 66% of respondents; 54% observed no response. Complete remission in >50% of patients was reported by 41% of the respondents. FSGS recurrence after transplantation is common, but varies greatly between centers. We found great variability in preventive and therapeutic treatment regimens. Future research should focus on predisposing factors, including biopsy findings and genetic mutations, and standardized treatment.

Results of a Pediatric Transplant Program in a Low Income Country

Background Since the middle of the last decade, the incidence of ESRD has been relatively stable for many affluent countries such as USA and Western European countries. However, rates appear to be increasing for many developing countries, becoming more challenging to get access to Renal Replacement Therapy (RRT), and transplant in particular. As an example, Guatemala has a kidney transplant rate of 6.9 per million population (pmp) per year, including children and adults, compare to Spain where it is more than 34 pmp. Guatemala, situated in Central America, with 16 million populations has an incidence of ESRD in children of 4.6 per million age-related population (pmarp). FUNDANIER (Foundation for Children with Kidney Diseases) has become the only center that provides free access to comprehensive RRT to Guatemalan Children, including transplantation and immunosuppression. As the national referral center for pediatric RRT, FUNDANIER provides peritoneal dialysis (40.4% of patients), hemodialysis (26.4%), transplant, (12.4%), and conservative management (no RRT) in 17.6%. The transplant program was founded in 2007, and has performed and follow more than eighty transplants. With the goal of presenting the results of this experience, we analyzed the pediatric transplant program database. Methods Data from recipients and donors were described as qualitative (Sex, etiology of ESRD, RRT before transplant, type of donors, type of induction, immunosuppression protocol, reasons for discharge of the program, causes of graft loss and acute and relevant complications) and quantitative variables (number of transplant and number. of rejections) using proportions. Mean and standard deviation were used for quantitative variables such as age, follow up time and eGFR. We retrospectively described the results of all transplanted patients between 2007 and 2017. Results Eighty three patients were followed. 78 were transplanted at our center and five were referred for follow up. The mean age was 12.49 years (SD 3.28), 53% were male and the etiology of ESRD was unknown in 63%, followed by CAKUT in 23% of patients. Most of the donations were from living donors (88%). Infections were the most common acute complication after transplant (n=16/80, 20%). In total 25% of patients (18/73) experience at least 1 episode of rejection during 12 months post transplant. Of 47 episodes of rejection reported, 49% (23/47) were after 1 year post transplant. 8/37 (22%) patients discharged from the program were moved to other type of RRT due to graft loss. The patient and graft survival at 1 year was 90% and 88%. When divided by type of donation, the 1 year graft survival for living and deceased donor was 90% and 70%. Conclusion Our graft survival is comparable from pediatric kidney transplant program in low-middle income countries. Increasing the number of deceased donor is mandatory in order to improve the transplant rate in a country with a high rate of ESRD with unknown etiology.

NPHP1 (Nephrocystin-1) Gene Deletions Cause Adult-Onset ESRD.

Background Nephronophthisis (NPH) is the most prevalent genetic cause for ESRD in children. However, little is known about the prevalence of NPH in adult-onset ESRD. Homozygous full gene deletions of the NPHP1 gene encoding nephrocystin-1 are a prominent cause of NPH. We determined the prevalence of NPH in adults by assessing homozygous NPHP1 full gene deletions in adult-onset ESRD.Methods Adult renal transplant recipients from five cohorts of the International Genetics and Translational Research in Transplantation Network (iGeneTRAiN) underwent single-nucleotide polymorphism genotyping. After quality control, we determined autosomal copy number variants (such as deletions) on the basis of median log2 ratios and B-allele frequency patterns. The findings were independently validated in one cohort. Patients were included in the analysis if they had adult-onset ESRD, defined as start of RRT at ≥18 years old.Results We included 5606 patients with adult-onset ESRD; 26 (0.5%) showed homozygous NPHP1 deletions. No donor controls showed homozygosity for this deletion. Median age at ESRD onset was 30 (range, 18-61) years old for patients with NPH, with 54% of patients age ≥30 years old. Notably, only three (12%) patients were phenotypically classified as having NPH, whereas most patients were defined as having CKD with unknown etiology (n=11; 42%).Conclusions Considering that other mutation types in NPHP1 or mutations in other NPH-causing genes were not analyzed, NPH is a relatively frequent monogenic cause of adult-onset ESRD. Because 88% of patients had not been clinically diagnosed with NPH, wider application of genetic testing in adult-onset ESRD may be warranted.

Estimating Time to ESRD in Children With CKD

The KDIGO (Kidney Disease: Improving Global Outcomes) guideline for chronic kidney disease (CKD) presented an international classification system that ranks patients' risk for CKD progression. Few data for children informed guideline development. Observational cohort study. Children aged 1 to 18 years enrolled in the North American Chronic Kidney Disease in Children (CKiD) cohort study and the European Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of CRF in Pediatric Patients (ESCAPE) trial. Level of estimated glomerular filtration rate (eGFR) and proteinuria (urine protein-creatinine ratio [UPCR]) at study entry. A composite event of renal replacement therapy, 50% reduction in eGFR, or eGFR<15mL/min/1.73m2. eGFR was estimated using the CKiD-derived "bedside" equation. Accelerated failure time models of the composite outcome using a conventional generalized gamma distribution. Likelihood ratio statistics of nested models were used to amalgamate levels of similar risk. Among 1,232 children, median age was 12 (IQR, 8-15) years, median eGFR was 47 (IQR, 33-62) mL/min/1.73m2, 60% were males, and 13% had UPCRs>2.0mg/mg at study entry. 6 ordered stages with varying combinations of eGFR categories (60-89, 45-59, 30-44, and 15-29mL/min/1.73m2) and UPCR categories (<0.5, 0.5-2.0, and >2.0mg/mg) described the risk continuum. Median times to event ranged from longer than 10 years for eGFRs of 45 to 90mL/min/1.73m2 and UPCRs<0.5mg/mg to 0.8 years for eGFRs of 15 to 30mL/min/1.73m2 and UPCRs>2mg/mg. Children with glomerular disease were estimated to have a 43% shorter time to event than children with nonglomerular disease. Cross-validation demonstrated risk patterns that were consistent across the 10 subsample validation models. Observational study, used cross-validation rather than external validation. CKD staged by level of eGFR and proteinuria characterizes the timeline of progression and can guide management strategies in children.

Association of variable number tandem repeats polymorphism in the IL-4 gene with end-stage renal disease in children

BackgroundEnd stage renal disease (ESRD) is a common cause of morbidity and mortality among children. Interleukin 4 is a cytokine that might influence the progression of chronic kidney disease (CKD) to end stage renal disease. There are variable number of tandem repeats (VNTRs) in IL4 gene that could play major roles in genetic predisposition to some diseases. Aim of the study: The purpose of this study is to detect the association of allelic variant in intron 3 VNTR-IL4 gene with the end stage renal disease and if these variants could be considered as risk markers for this disease. Subjects and methodsThe study was conducted on fifty-five children with CKD and fifty healthy children served as controls. All participants were genotyped for intron 3 VNTR by Polymerase Chain Reaction. ResultsThe frequency of intron 3 VNTR-IL4 P1P2+P2P2 genotypes was significantly higher in ESRD-children than those with P1P1 genotype (88.7% vs. 15.4%, OR 43; 95% CI 13–134, P value<0.001). Also, the frequency of P2 allele was significantly higher in ESRD-children compared with healthy controls (70.9% vs. 8%, OR 28; 95% CI 12–64, P value<0.001). Furthermore, a significantly higher frequencies of P1P1 genotype and P1 allele among the control group were demonstrated (84.6% vs. 11.3%, P<0.001 and 92% vs. 29.1%, P<0.001, respectively). Conclusionwe concluded that the P2 allele is an allelic variant predisposing to ESRD in children with CKD and it could be considered a risk factor for the development of ESRD.

A Predictive Model of Progression of CKD to ESRD in a Predialysis Pediatric Interdisciplinary Program

The incidence of ESRD in children has increased over the last two decades. Nevertheless, there are still limited data on risk factors related to the emergence of ESRD among patients with CKD. The aim of this study was to develop a model of prediction of ESRD in children and adolescents with CKD (stages 2-4) enrolled in a predialysis interdisciplinary management program. In this retrospective cohort study, 147 patients with CKD admitted from 1990 to 2008 were systematically followed up at a tertiary pediatric nephrology unit for a median of about 4.5 years. The primary outcome was the progression to CKD stage 5. A predictive model was developed using Cox proportional hazards model and evaluated by c statistics. The median renal survival was estimated at 98.7 months (95% confidence interval [95% CI], 68.7 to 129.6 months). The probability of reaching CKD stage 5 was estimated as 52% in 10 years. The most accurate model included eGFR, proteinuria at admission, and primary renal disease. Risk score ranged from 0 to 13 points (median, 4 points). The accuracy of the score applied to the sample was high, with c statistics of 0.865 (95% CI, 0.80 to 0.93) and 0.837 (95% CI, 0.76 to 0.91) at follow-up of 2 and 5 years, respectively. By survival analysis, it was estimated that at 10 years after admission, the probability of renal survival was about 63% for patients in the low-risk group and 43% for the medium-risk group; all patients assigned to the high-risk group had CKD stage 5 (P<0.001). The predictive model of progression of CKD might contribute to early identification of a subgroup of patients at high risk for accelerated renal failure.

Timing and Outcome of Renal Replacement Therapy in Patients with Congenital Malformations of the Kidney and Urinary Tract

Congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of ESRD in children, but the proportion of patients with individual CAKUT entities progressing to ESRD during adulthood and their long-term clinical outcomes are unknown. This study assessed the age at onset of renal replacement therapy (RRT) and patient and renal graft survival in patients with CAKUT across the entire age range. Patients with CAKUT were compared with age-matched patients who were undergoing RRT for other renal disorders on the basis of data from the European Renal Association-European Dialysis and Transplant Association Registry. Competing risk and Cox regression analyses were conducted. Of 212,930 patients commencing RRT from 1990 to 2009, 4765 (2.2%) had renal diagnoses consistent with CAKUT. The proportion of incident RRT patients with CAKUT decreased from infancy to childhood and then increased until age 15-19 years, followed by a gradual decline throughout adulthood. Median age at RRT start was 31 years in the CAKUT cohort and 61 years in the non-CAKUT cohort (P<0.001). RRT was started earlier (median, 16 years) in patients with isolated renal dysplasia than in those with renal hypoplasia and associated urinary tract disorders (median, 29.5-39.5 years). Patients with CAKUT survived longer than age- and sex-matched non-CAKUT controls because of lower cardiovascular mortality (10-year survival rate, 76.4% versus 70.7%; P<0.001). CAKUT leads to ESRD more often at adult than pediatric age. Treatment outcomes differ from those of acquired kidney diseases and vary within CAKUT subcategories.

Characteristics and Outcomes of Children with Primary Oxalosis Requiring Renal Replacement Therapy

Primary hyperoxaluria (PH) as a cause of ESRD in children is believed to have poor outcomes. Data on management and outcomes of these children remain scarce. This study included patients aged <19 years who started renal replacement therapy (RRT) between 1979 and 2009 from 31 countries providing data to a large European registry. Of 9247 incident patients receiving RRT, 100 patients had PH. PH children were significantly younger than non-PH children at the start of RRT. The median age at RRT of PH children decreased from 9.8 years in 1979-1989 to 1.5 years in 2000-2009. Survival was 86%, 79%, and 76% among PH patients at 1, 3, and 5 years after the start of RRT, compared with 97%, 94%, and 92% in non-PH patients, resulting in a three-fold increased risk of death over non-PH patients. PH and non-PH patient survival improved over time. Sixty-eight PH children received a first kidney (n=13) or liver-kidney transplantation (n=55). Although the comparison was hampered by the lower number of kidney transplantations primarily derived from the earlier era of RRT, kidney graft survival in PH patients was 82%, 79%, and 76% at 1, 3, and 5 years for liver-kidney transplantation and 46%, 28%, and 14% at 1, 3, and 5 years for kidney transplantation alone, compared with 95%, 90%, and 85% in non-PH patients. The outcomes of PH children with ESRD are still poorer than in non-PH children but have substantially improved over time.

Pro- and Anti-Inflammatory Cytokines in Chronic Pediatric Dialysis Patients

Dialysis provides effective and safe treatment of ESRD in children, but patients who are maintained on chronic dialysis are at risk for cardiovascular disease. One major risk factor for cardiovascular disease in adult patients with ESRD is chronic inflammation. The effect of anti-inflammatory therapy with aspirin on serum cytokine concentration was studied in seven children who were receiving hemodialysis (HD) and seven who were receiving continuous cycling peritoneal dialysis (CCPD or PD). Dialysis vintage was 4.3 +/- 4.6 yr; single-pool Kt/V was 1.46 +/- 1.4, mean equilibrated Kt/V was 1.27 +/- 0.16, and PD weekly Kt/V was 2.45 +/- 0.30. Baseline proinflammatory cytokine IL-1beta, IL-6, IL-8, and TNF-alpha serum concentrations were significantly elevated, whereas serum anti-inflammatory cytokine IL-4 and IL-10 concentrations were normal. The patterns of cytokine elevation were similar for patients who were receiving HD versus PD. IL-4 and IL-6 concentrations demonstrated strong positive correlation with dialysis vintage (IL-4, P < 0.03; IL-6, P < 0.0001). Pre-aspirin serum cytokine concentrations did not vary with single-pool Kt/V or equilibrated Kt/V for HD patients or with weekly Kt/V for PD patients. Serum IL-8 and TNF-alpha concentrations were significantly reduced by aspirin treatment at 4 mo (P = 0.04 and P = 0.007, respectively). Serum IL-6 concentration decreased with aspirin treatment but not significantly (P = 0.1). Serum IL-1beta concentration remained unchanged, and IL-4 and IL-10 concentrations remained stable throughout aspirin treatment. The effect of aspirin treatment on serum cytokine concentrations was similar for HD and PD patients. In HD patients, IL-6, IL-8, and TNF-alpha remained suppressed 1 mo after discontinuation of aspirin. It is concluded that proinflammatory cytokines are elevated in pediatric HD and PD patients without counterbalance from anti-inflammatory cytokines, and aspirin therapy attenuates inflammation.

6 Identifying the Mouse Gene Responsible for Congenital Progressive Hydronephrosis (CPH).

Obstructive uropathy is the leading cause of chronic renal failure and ESRD in children. Understanding the genetic and molecular control of urinary tract development is critical for making an impact on obstructive uropathy. Presently, little is known about the specific molecular causes of obstructive uropathy.The congenital progressive hydronephrosis (cph) mouse was described as having a random recessive mutation in the C57Bl/6J strain of mice in 1978 and was crudely mapped to mouse chromosome 15 between the visible markers belted (bt) (now ADAMTS20) and Caracul (Ca) (now Krt2–6g). The cph mutant provides an excellent model of obstructive uropathy that closely mimics the process in humans. The renal phenotype of homozygous cph mutants is not grossly visible at day 1 of age but can be detected microscopically with abnormalities of the renal papillae indicating onset in-utero. Radiographic analysis demonstrates profound hydronephrosis with obstruction at the level of the UPJ.We hypothesize that the identification of the cph gene and mutation therein, will provide novel insight into the mechanism of development of congenital progressive hydronephrosis and allow identification of important signaling molecules required for both normal and abnormal genitourinary tract development.Obligate heterozygote mice for cph, were mated to the 129Ola strain of mice to generate F1 progeny containing the cph mutation. Random F1 animal matings has resulted in the generation of F2 mice homozygous for the cph mutation. DNA samples from F2 mice homozygous for the cph mutation have been used for analysis. We have obtained multiple cph mutants on this F2 background and we have begun linkage analysis using SSLP markers in the candidate region on Chromosome 15. Through cross-over analysis using MIT markers we have narrowed the region of the mutation on Chromosome 15. We have found a marker, D15Mit172, very close to the proposed genomic location of the cph gene that is consistently inherited as homozygous for the B6 allele in all affected F2 animals genotyped, giving 100% concordance with this marker and the cph phenotype in seven of fifty-one F2 mice to date. This finding leads us to believe that the D15Mit172 marker can be used as a proxy locus for genotyping embryos in the F2 genetic background for in-utero analyses. Simultaneous candidate gene sequencing and Real Time RT-PCR analysis has been performed and narrowed the candidate field. A promising gene has been identified.

Insulin-like growth factor (IGF) and IGF binding protein gene expression in multicystic renal dysplasia.

Multicystic dysplastic kidney disease is the most common form of renal dysplasia that leads to ESRD in children. This study describes the histopathological changes of multicystic dysplasia that occur from early fetal life to the postnatal period. At 14 wk gestation, early cystic enlargement of various segments of the nephron have been identified, in addition to a displaced metanephric blastema adjacent to zones of normal nephrogenesis. At later stages, the predominant features include cyst enlargement with marked fibromuscular collars, architectural disorganization, and replacement of the interstitium with a disarray of mesenchymal tissue. This study investigated the expression of the mRNA encoding the insulin-like growth factors (IGF) and IGF binding proteins (IGFBP) and have demonstrated IGF-II, IGFBP-2, and IGFBP-3 to be altered. Apart from their expression in the displaced metanephric blastema, both IGF-II and IGFBP-2 were overexpressed in abnormal tissue elements in all kidneys from fetal to postnatal life. IGF-II gene expression was localized to mesenchymal tissue, specifically in the periductal fibromuscular collars. IGFBP-2 mRNA was found to be expressed exclusively in the cyst epithelia of all cysts at all ages studied, whereas IGFBP-3 mRNA was absent from these epithelia. This study details the failure of normal IGF expression in the development of multicystic renal dysplasia and suggests a role for the IGF system in the progressive histopathological changes of this disorder.